Rheumatoid synovial fluid is characterized by an infiltrate of T cells that display markers of recent activation, while at the same time they are refractory to mitogenic stimulation. For example, the activation marker CD69 is constitutively expressed on the majority of SF T cells; however, stimulating the CD69 activation pathway does not induce cytokine production and cell proliferation. In addition, CD69, expressed on SF T cells, is capable of inducing TNF-alpha production from SF monocytes. This novel pathway leading to TNF-alpha production involves an unknown receptor on the surface of monocytes that is specific for CD69. Thus, on SF T cells CD69 appears to serve as a ligand that induces proinflammatory cytokine production by acting through a receptor on the surface of SF monocytes. An understanding of this new pathway may lead to novel approaches to inhibiting TNF production in rheumatoid synovium. The experiments in this proposal are designed to provide an understanding of the biochemical and molecular character of the CD69 receptor expressed on monocytic cells. These experiments will lead to a better understanding of the role of T cells in the initiation and progress of rheumatoid arthritis, and could lead to the identification of new biological targets for therapeutic intervention.